Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy

Abstract

The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine-protein kinase, which regulates many biological processes related to metabolism, cancer, immune function, and aging. It is an essential protein kinase that belongs to the phosphoinositide-3-kinase (PI3K) family and has two known signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Even though mTOR signaling plays a critical role in promoting mitochondria-related protein synthesis, suppressing the catabolic process of autophagy, contributing to lipid metabolism, engaging in ribosome formation, and acting as a critical regulator of mRNA translation, it remains one of the significant signaling systems involved in the tumor process, particularly in apoptosis, cell cycle, and cancer cell proliferation. Therefore, the mTOR signaling system could be suggested as a cancer biomarker, and its targeting is important in anti-tumor therapy research. Indeed, its dysregulation is involved in different types of cancers such as colon, neck, cervical, head, lung, breast, reproductive, and bone cancers, as well as nasopharyngeal carcinoma. Moreover, recent investigations showed that targeting mTOR could be considered as cancer therapy. Accordingly, this review presents an overview of recent developments associated with the mTOR signaling pathway and its molecular involvement in various human cancer types. It also summarizes the research progress of different mTOR inhibitors, including natural and synthetised compounds and their main mechanisms, as well as the rational combinations with immunotherapies.

Keywords: cancer; immunotherapy; mTOR; mTOR inhibitors; natural drugs.

Figure 1

The structural domains of mTOR are shown hierarchically in this schematic. The HEAT domain, which is comprised of Huntingtin, elongation factor 3, subunit A of PP2A, and Tor1p; the FAT domain, which is comprised of FRAP-ATM-TRAPP; the FRB domain, which is comprised of FKBP12-rapamycin binding; and the FATC domain are the evolutionarily conserved structural domains of mTOR (FAT C-terminus). There are a total of 2549 amino acids found in the entire polypeptide sequence of mTOR. (A) Constituents of mTORC1: Important to the complex is the mTOR-interacting protein with the DEP domain (mLST8). The protein DEPTOR (mTOR-interacting protein) functions as an endogenous inhibitor of mTORC1. The mTOR-regulatory associated protein (Raptor), which has its own HEAT repeats and binds to mTOR, is the essential component of mTORC1. Moreover, in response to insulin, raptor recruits PRAS40, a proline-rich 40 kDa AKT substrate that suppresses mTORC1 activity. (B) mLST8, DEPTOR, and RICTOR, the defining component of mTORC2, are subunits of mTORC2. The rictor protein interacts with rictor-associated protein 1 and 2, which act as scaffolding proteins (RICTOR 1). Addition of PROTOR1/2, a pleckstrin homology domain-containing protein, and mSIN1, a MAPK interaction protein, to the complex.

Figure 2

The mTOR pathway. mTORC1, also known as the rapamycin-sensitive complex, is made up of four proteins: mTOR, raptor, mLST8, and PRAS40. TSC1/2-Rheb is mTORC1’s primary upstream regulator. mTORC1 regulates protein translation by phosphorylating S6K1 and 4EBP1 via the TSC1/2-Rheb axis, which integrates cellular energy levels, growth hormones, and Wnt signals. Rheb, TSC1/2, AMPK, Rag, and Akt are the key upstream regulators of mTORC1. When mTORC1 is active at the lysosome membrane, it phosphorylates 4E-BP1, S6K, SREBP, and some autophagy components, all of which influence protein synthesis, lipid and lysosome production, energy metabolism, and autophagy. On the other hand, little is known about mTORC2’s upstream regulators.